Increased rates of proliferation form the earliest and, most probably, the necessary background for the transformation of a normal colonic epithelium to cancer. Chronic intestinal inflammation, especially of the colon, also significantly increases risk of developing cancer. However, the complex inter-relationships among inflammation, proliferation and neoplasia generation, is less well understood. We have employed a mouse model (Transmissible Murine Colonic Hyperplasia, TMCH) to study how pro-inflammatory cytokines and dietary butyrate regulate nuclear factor-(B (NF-kappaB) and beta-catenin mediated increases in cell census in the native colonic mucosa. TMCH is characterized by epithelial hyperproliferation and hyperplasia. Depending upon the genetic background, varying degrees of inflammation occur with pathophysiological similarities to human inflammatory gastrointestinal diseases. In outbred mice, onset of TMCH was preceded by transient increases in TNF-alpha and IFN-gamma, and parallel mitogenic changes in mucosal beta-catenin abundance, phosphorylation and downstream targets (cyclin Dl, c-myc) signaling. Changes in NF-kappaB activity /nuclear translocation followed TNF-alpha expression. Dietary pectin (source of butyrate) abrogated the hyperplastic responses during TMCH. In genetically susceptible C3H/HeNHsd (C3H) inbred mice, a chronic inflammation associated with dramatic increases in intra-epithelial CD3+/CD 103+ T cells, could be seen in the entire colon. Based on these findings, we aim to: 1. Determine how TNF-alpha and butyrate modulate beta-catenin/NF-kappaB expression/activity, sub-cellular distribution, and signaling in the non-inflamed colonic mucosa; 2. Determine how TNF-alpha and butyrate modulate beta-catenin/NF-kappaB expression/activity, subcellular distribution, and signaling during chronic inflammation. To accomplish these goals, we intend to utilize in vivo neutralizing TNF-alpha antibody and direct colonic mucosal exposure to Eudagrit coated sodium butyrate pellets. These studies will help us delineate how TNF-alpha and butyrate individually modulate beta-catenin/NF-kappaB mediated hyperproliferation /inflammation and subsequent mucosal priming for carcinogenesis. By studying a mechanistic basis of NF-kappaB and beta-catenin mediated increases in cell census, in the absence and presence of chronic inflammation, we may identify new treatment strategies for reducing cancer risk.